tbuckley/cabot-search huggingface dataset:
White matter penetrating arteriole dysfunction correlates with MRI-defined white matter integrity in patients with Alzheimer's disease
Authors: ZSOLT Bagi, C Kroenke, CD Keene, LS Sherman, SA Back
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Institute of Health Objectives Patients with Alzheimer’s Disease (AD) display cerebral white matter (WM) hyperintensities in association with microvascular brain injury (mVBI) and cerebral microinfarcts. We determined the extent to which vasomotor dysfunction of WM penetrating arterioles is associated with mVBI in autopsy brains from patients with low or high AD neuropathology, and determined if these changes correlate with quantitative indices of MRI-defined WM integrity. Methods We analyzed 28 consecutive cases of prefrontal rapid autopsies in a population-based cohort with low or high AD neuropathological changes, and with or without cerebral microinfarcts (mVBI). WM penetrating and pial surface arteriolar responses to the endothelium-dependent agonist, bradykinin were assessed ex vivo with videomicroscopy. Expression of vascular endothelial nitric oxide synthase (eNOS) and NAD(P)H-oxidase (Nox1,2 and 4 isoforms) was measured with quantitative PCR. Diffusion tensor imaging was used to measure mean apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in post-mortem prefrontal WM. Results Patients with high AD neuropathology and mVBI exhibited a significantly reduced dilation in response to bradykinin selectively in WM arterioles, when compared to low or high AD cases without mVBI or to pial surface arterioles. Expression of eNOS was reduced, whereas Nox-1 expression was increased in WM arterioles in AD and mVBI cases. Moreover, we found that in cases with low AD pathology the magnitude of bradykinin-induced WM arteriole dilation was correlated with higher FA and lower ADC. In contrast, dilation to bradykinin was associated with lower FA and higher ADC in cases with high AD neuropathology. Interpretation: Selectively impaired vasodilation to the endothelium-dependent agonist, bradykinin occurs in WM penetrating arterioles in AD patients with WM microinfarcts, which is likely due to reduced nitric oxide and an increase in Nox1-derived reactive oxygen species production. Notably, the bradykinin response of WM arterioles strongly correlated with MRI-defined WM integrity suggesting that impaired bradykinin-mediated vasodilation in WM penetrating arterioles contributes to disrupted white matter microstructural integrity as defined by MRI.
3-year outcomes from the prospective ‘MRIAS’ trial: A novel active surveillance protocol which incorporates multiparametric MRI to reduce frequency of biopsy in men with prostate cancer
Authors: P.N. Doan, M.J. Scheltema, A.A. Amin, R. Shnier, B. Geboers, W. Gondoputro, D. Moses, P.J. Van Leeuwen, A-M. Haynes, J. Matthews, P. Brenner, G. O'Neill, C. Yuen, W. Delprado, P. Stricker, J. Thompson
Journal: European Urology (2022)
QOL-27. Sociocultural variables have a major impact on participation in patients treated for pediatric posterior fossa tumors
Authors: Doris Hoffmann-Lamplmair, Alexandra Gram, Kerstin Krottendorfer, Andreas Peyrl, Ulrike Leiss, Thomas Czech, Irene Slavc, Thomas Pletschko
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE: This study investigates the extent of participation barriers in patients with pediatric posterior fossa tumors (PFTs) at long-term follow-up. While most studies focus on pathobiological variables that promote the occurrence of adverse late effects, the present analysis aims to investigate the importance of environmental variables. METHOD: Ten years after tumor diagnosis, 42 patients (mean age: 17 years) treated at our pediatric neuro-oncology unit were assessed for school and social difficulties using a questionnaire developed within the framework of this study. Participation barriers were assumed if patients and/or their parents reported difficulties at school or with peers. The children and adolescents were classified into groups with adequate and limited participation. Potential pathobiological (treatment type, hydrocephalus, tumor recurrence, gender, age at diagnosis, seizures, cerebellar mutism) and environmental risk factors (parental and maternal education, siblings, primary language, discrepancies between personal and environmental values, regular physical activity, private housing) were identified and examined to see if the participation groups differed in the amount of risk factors. RESULTS: Almost a decade after treatment, two thirds of the patients had school and/or social difficulties. Not only pathobiological risk factors (type of treatment, hydrocephalus, tumor recurrence, cerebellar mutism and seizures), but also environmental factors (low maternal education level, siblings, a main language other than German, discrepancies between social and personal values, and irregular physical activity) were associated with limited participation. These variables discriminated significantly between patients with and without participation barriers. CONCLUSION: Participation barriers in patients treated for pediatric PFT are frequent. In addition to pathobiological variables, environmental risk factors also play an important role in limiting school and social participation. This underlines the fact that a sole consideration of pathobiology is not sufficient when examining risk factors for the occurrence of late effects. The adoption of biopsychosocial perspectives in future studies is inevitable.
Approach for reporting master protocol study designs on ClinicalTrials.gov: qualitative analysis
Authors: Rebecca J Williams, Heather D Dobbins, Tony Tse, Sandy D Chon, David Loose, Gisele A Sarosy, Sheila A Prindiville, Frank W Rockhold, Deborah A Zarin
Journal: BMJ (2022)

Abstract Objective To describe an approach for reporting master protocol research programs (MPRPs) that is consistent with existing good reporting practices and that uses structured information to convey the overall master protocol and design of each substudy. Design Qualitative analysis. Data sources ClinicalTrials.gov trial registry. Main outcome measures Established goals and related practices of the trial reporting system were outlined, examples and key characteristics of MPRPs were reviewed, and specific challenges in registering and reporting summary results to databases designed for traditional clinical trial designs that rely on a model of one study per protocol were identified. Results A reporting approach is proposed that accommodates the complex study design of MPRPs and their results. This approach involves the use of separate registration records for each substudy within one MPRP protocol (with potential exceptions noted). Conclusions How the proposed approach allows for clear, descriptive, structured information about each substudy’s prespecified design and supports timely reporting of results after completion of each substudy is described and illustrated. Although the focus is on reporting to ClinicalTrials.gov, the approach supports broader application across trial registries and results databases. This paper is intended to stimulate further discussion of this approach among stakeholders, build awareness about the need to improve reporting of MPRPs, and encourage harmonization across trial registries globally.
Machine-derived data and molecular markers as indicators of organ quality in normothermic machine perfusion with whole blood
Authors: A.E. Yakaç, C. Steinhauser, J. Putz, S. Füssel, S. Kromnik, W. Markgraf, R. Mühle, P. Talhofer, A. Döcke, H. Malberg, C. Thiele, C. Thomas
Journal: European Urology (2022)
Emerging immuno-therapies for advanced pancreatic cancer: An overview of available literature.
Authors: Adeel Masood, Hamid Ehsan, Qamar Iqbal, Saher Nasir Amin, Melissa Wilson
Journal: Journal of Clinical Oncology (2022)

e16231 Background: Pancreatic cancer is the 11 th most common cancer and represents 3.2% of all new cancer cases. But it is the third leading cause of cancer-related deaths with a five-year relative survival of only 10.8%. More than 50% of patients diagnosed with metastatic disease at initial presentation have 5-year relative survival of only 3.0%. Here, we explore the recent literature for the emerging role of immunotherapies and their outcomes for advanced pancreatic cancer. Methods: The literature search was conducted on PubMed, Embase, Cochrane, and ClinicalTrials.gov from inception to January 2022 using MeSH terms' pancreatic neoplasms', 'immunotherapy,' and 'therapeutics'. The final analysis includes nine clinical trials that meet the inclusion criteria regarding immunotherapy for metastatic pancreatic cancer. Results: The combination of pembrolizumab and trametinib with stereotactic radiotherapy (SBRT) reported a median progression-free survival (PFS) and overall survival (OS) of 25 and 18 months compared to gemcitabine and SBRT combination of 22 and 16 months, respectively. Another study reported a median OS of 18 months with nivolumab along with operative irreversible electroporation to increase the bioavailability of nivolumab in the cancer cells. The EGFR targeted CAR T cells therapy was evaluated in 14 patients with advanced pancreatic cancer with a median OS of five months and an overall response rate (ORR) of 29%. Sotigalimab, an agonistic CD40 antibody combined with nivolumab, was found to have an ORR of 58%, PFS of 12 months, and OS of 20 months after a follow-up of almost 18 months. On the contrary, Bruton's tyrosine kinase inhibitors such as Acalabrutinib and Ibrutinib were found to have no OS benefit (median OS 3.8 and 5.3 months, respectively). Conclusions: Due to the high mortality associated with advanced pancreatic cancer, there is increasing interest in Novel immunotherapies-based approaches, with some showing promising results.[Table: see text]
Rural-urban disparities in Geriatric Assessment (GA) impairments and mortality among older adults with cancer: Results from the Cancer and Aging Resilience Evaluation (CARE) Registry.
Authors: Mackenzie Fowler, Kelly Kenzik, Mustafa Al-Obaidi, Christian Harmon, Smith Giri, Sankalp Arora, Moh'd M. Khushman, Darryl Alan Outlaw, Smita Bhatia, Grant Richard Williams
Journal: Journal of Clinical Oncology (2022)

12012 Background: Rural-urban disparities persist in cancer incidence and mortality, despite improvement in cancer screening and treatment. Older adults are at increased risk for cancer, represent the majority of cancer cases, and are more likely to reside in rural areas than younger adults are. GAs are recommended in clinical management of older adults with cancer, in part to identify aging-related impairments predictive of adverse outcomes; few studies have explored rural-urban disparities in GA impairments and mortality among older patients with cancer. Methods: We included 937 older adults (≥60y) from the CARE registry recently diagnosed with cancer who underwent GA at their first pre-chemotherapy visit to the UAB oncology clinic. Rural-urban status using Rural-Urban Commuting Area (RUCA) codes, classified the cohort by residence in metropolitan, micropolitan, and rural/small town areas. We included self-rated performance status (PS) (≥2 on Eastern Cooperative Oncology Group PS), instrumental activities of daily living (IADL) [≥1 impairment], physical and mental health-related quality of life (HRQoL) [t-score &lt; 40 on PROMIS 10-item Global Health], and overall survival as outcomes. Logistic regression evaluated the association between rural-urban status and each outcome (except overall survival, where we used Cox regression analyses). Micropolitan residence was chosen as the reference category due to similar high risk in both rural and urban areas. Results: Median age at study participation was 69.0y (Interquartile range: 64.0-74.0); 12.4% resided in rural, 14.8% in micropolitan and 72.8% in urban areas; 22.5% were diagnosed with colorectal cancer, 19.0% with pancreatic, and 12.4% with hepatobiliary; 74.7% were Stage III/IV. Participants in rural areas were more likely to be white and less educated. After adjustment for age, sex, race, education and cancer type/stage, rural residence was associated with increased odds of impaired PS (OR = 1.93, 95% CI: 1.10-3.40), limitations in IADLs (OR = 1.79, 95% CI: 1.03-3.10), and impaired physical HRQoL (OR = 1.84, 95% CI: 1.05-3.22) compared to micropolitan residence. Urban residence was not significantly associated with any GA outcomes compared to micropolitan residence. Rural residence was associated with higher hazard of death compared to micropolitan residence (HR = 1.88, 95% CI: 1.09-3.24) as well as urban residence (HR = 1.67, 95% CI: 1.13-2.45). Conclusions: Among older adults with newly diagnosed cancer, rural residence was associated with impaired PS, limitations in IADLs, impaired physical HRQoL, and reduced overall survival. Implementation of routine GA among older adults in rural areas may aid in early identification and intervention on GA impairments to improve cancer outcomes.
Risk of orgasmic function impairment after HoLEP – findings of a prospective real-life trial (ExpHo)
Authors: P. Capogrosso, E. Ventimiglia, G. Fallara, A. Costa, F. Pellegrino, L. Candela, E. Pozzi, F. Belladelli, M. De Angelis, G. Colandrea, W. Cazzaniga, D. Cignoli, N. Schifano, R. Matloob, F. Degò, V. Scattoni, A. Salonia, F. Montorsi
Journal: European Urology (2022)
Genomic landscape and clonal evolution between adenocarcinoma and squamous components in adenosquamous carcinoma of the pancreas.
Authors: Zheng Wang, Shiwei Guo, Yina Jiang, Yinying WU, Zheng Wu, Qingyong Ma, Yan Wang, Liwen Zhang, Dong You
Journal: Journal of Clinical Oncology (2022)

e16265 Background: Adenosquamous carcinoma of the pancreas (ASCP) is a rare histological subtype of pancreatic cancer with high metastasis rate and poor prognosis, which is characterized by a variable proportion of adenocarcinoma and squamous carcinoma components with at least 30% of the tumor showing squamous differentiation. To get further insight into the tumorigenesis and progression, we profiled the genetic characterization and explored the evolutionary model of this subtype. Methods: A total of 10 patients with ASCP were enrolled. For each sample, glandular and squamous carcinoma tissues were separated by microdissection. Whole exome sequencing for 20 samples with matched peri-carcinomatous tissues were performed by next-generation sequencing. Results: Genetic profiling revealed that top 5 mutated genes of adenocarcinoma and squamous components were highly consistent including TP53 (100% vs 100%), KRAS (100% vs 90%), CDKN2A (40% vs 40%), KDM6A (20% vs 20%) and LRP1B (20% vs 20%). KEGG pathway analysis showed that PI3K-Akt, MAPK and FoxO signaling pathways were the most frequently mutated pathways in adenocarcinoma. In contrast, Apelin and Rap1 signaling pathways were highly mutated in squamous components, advocating that these pathways may play important roles in the transformation of squamous carcinomas. A higher proportion of indels were identified in adenocarcinoma than squamous components (12.1% vs 3%). The chromosome regions of 3p21.3, 9p21.3, 11p15.5, 16p13.11 and 21q22.3 were the most commonly deleted regions in the adenocarcinoma components, while losses of 1p36.21, 3p25.3, 3q13.13, 6p22.3 and 11p15.5 had been observed in the squamous components. Some of these regions had important effects on development and progression of cancer. For example, 9p21.3 had well-established impact on cell proliferation and apoptosis containing two crucial tumor suppressor genes, CDKN2A and CDKN2B. Additionally, the C &gt; T mutation was predominant among the 6 types of single nucleotide variations. Most common signatures were related to aging (Single base substitutions, SBS1), BRCA1/2 mutations and responders to platinum therapy (SBS3), and defective DNA mismatch repair (SBS6). Tumor evolution analysis showed that the glandular and squamous components shared a common origin. There were two evolutionary scenarios in the early stages of tumor evolution, with a third of nine patients ware parallel evolution and the remaining patients were linear evolution. KRAS (100%), TP53 (66.7%) and TTN (33.3%) were frequently identified as clonal mutations. Conclusions: This is the first study to elucidate the genomic alteration as well as the clonal evolution using whole-exome sequencing in ASCP patients. It provides evidence for more comprehensive understanding of pathophysiology of ASCP at genomic level, which could contribute to the amelioration for ASCP patients’ management.
EMRseq: Registry-based outcome analysis on 1,000 patients with BRAF V600–mutated metastatic melanoma in Europe treated with either immune checkpoint or BRAF-/MEK inhibition.
Authors: Michael Weichenthal, Inge Marie Svane, Lidija Kandolf Sekulovic, Joanna Mangana, Peter Mohr, Ivan Marquez-Rodas, Henrik Schmidt, Dimitrios C. Ziogas, Marc Bender, Eva Ellebaek, Kristina Urch, Gergana Shalamanova-Deleva, Iva Gavrilova, Enrique Espinosa, Reinhard Dummer, Piotr Rutkowski, Paolo Antonio Ascierto, Helen Gogas, Dirk Schadendorf, Lars Bastholt
Journal: Journal of Clinical Oncology (2022)

9540 Background: In BRAF mutated metastatic melanoma, potential outcome differences for different choices of 1 st line treatments including immunotherapy or BRAF-/MEK inhibition are not completely understood. We therefore analyzed the treatment patterns and outcome of systemic therapies for patients BRAF mutated metastatic melanoma. Methods: From the EUMelaReg treatment registry, patients fulfilling the following inclusion criteria were consecutively included until a number of 1,000 evaluable cases was reached. 1) Patients with metastatic melanoma and BRAF V600 mutation 2) First line treatment with either combined BRAF-/MEK or immune checkpoint inhibition (ICI) with PD-1 single agent or combined PD-1/CTLA-4 antibodies. Multivariable cox regression analysis as well as propensity score based weighting were used to control for bias from baseline imbalances. Primary outcomes of interest were overall survival (OS) and 2 nd line PFS (PFS-2), stratified for upfront treatment decision of ICI versus targeted therapy. PFS-2 was defined as the interval from start of first line treatment to a progression after a 2 nd line treatment or death of any cause. Further endpoints were evaluated including time on treatment (ToT), time to next treatment and 2 nd line treatments. Results: In total 529 (52.9 %) patients received BRAF/MEK-i, and 471 (47.1%) ICI. For various co-variates there were significant imbalances between strata, including number of metastatic sites, AJCC substage, serum LDH, and ECOG performance status, with more favorable prognostic variables for patients receiving immunotherapy. The ORR for BRAF/MEK-i was significantly higher than for ICI (53.3% vs. 42.0%; p=0.0004), but for OS and PFS2 the adjusted hazard ratios were significantly in favor for ICI (HR 0.62 and 0.66, respectively; p &lt;0.0001). In 2 nd line, patients switching from ICI to BRAF/MEK-i had again markedly higher ORR than patients switching vice versa (57.7% vs. 19.9%; P&lt;0.0001), and also significantly longer unadjusted PFS (8.1 vs. 3.1 months; p &lt;0.0001) and OS (15.7 vs. 10.6 mths; p=0.01) after start of 2 nd line treatment. Conclusions: The two cohorts had imbalances on key prognosis variables. After adjustment for these imbalances, upfront ICI still resulted in significantly longer OS as compared to BRAF/MEK-i. Due to the nature of real-world observational data causing inherent imbalances in the treatments cohorts and being unable to account for potential unknown confounders, outcome may still be biased despite adjustment efforts.[Table: see text]
Analysis of demographic characteristics and disparities of enrollment in cancer clinical research at the U.S. National Cancer Institute (NCI): A 15-year experience.
Authors: Nirmal Choradia, James L. Gulley, Charalampos S. Floudas
Journal: Journal of Clinical Oncology (2022)

6529 Background: Racial, gender, and socioeconomic disparities in cancer clinical trials participation have been well documented. The intramural program of the NCI in the National Institutes of Health (NIH) Bethesda campus conducts clinical research where participants are referred by their physician or self-referred, treated without charge and receive aid in travel expenses. We sought to describe the demographics of participants and identify potential disparities. Methods: We used the clinical research data repository of the NIH, Biomedical Translational Research Information System (BTRIS), to extract self-reported demographic data of enrollees in NCI protocols from 2005-2020. Comparisons were made with the U.S. population of patients with cancer as captured in the Surveillance, Epidemiology, and End Results (SEER) Program (2005-2018). The average household income per zip code was derived from the American Community Survey at five-year increments from 2011, 2015, and 2019. Results: We obtained data on 40,007 participants; 38,531 (95%) came from the U.S., of which 18,606 (48%) from DC, Maryland, or Virginia (DMV). Median age at consent was 54 years (range 2 – 89). Proportions of basic demographic attributes and corresponding values from SEER data were presented. Notably, Hispanic male, non-Hispanic female, and white female participants were under-represented in NCI clinical research compared to SEER data. African Americans were under-represented in the non-DMV population (5%) vs. the DMV (19%). Also, for patients from the DMV area, median income was consistently less for African American participants compared to White and Asian participants. Conclusions: The identified disparities may be partially due to the specific research activities available at the NCI, but strategies aiming at increasing the participation and representation of under-represented groups are required. [Table: see text]
DIPG-58. Therapeutic HDAC targeting in hypermutant CNS tumors
Authors: Carrie Myers, Alyssa Noll, Matthew Biery, Michael Meechan, Sophie Tahiri, Jessica Foster, Matthew Dun, James Olson, Nicholas Vitanza
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a universally fatal tumor of the pons, most often characterized by mutations in genes encoding histone 3, that led to the classification diffuse midline glioma, H3 K27M-mutant (DMG). However, 15% of DIPG are histone wildtype (H3WT) and can have a hypermutant phenotype, characterized by mutations in DNA mismatch repair that also occur in pediatric high-grade glioma (pHGG). We previously published the preclinical efficacy of quisinostat in DMG. As hypermutant CNS tumors share transcriptional disruption with DMG, we investigated if HDAC inhibition was also therapeutic against hypermutant DIPG and pHGG. We tested PBT-24, a PMS2 mutant, treatment-naïve, patient-derived hypermutant DIPG model, and found similar quisinostat sensitivity compared to other DMG cultures in vitro (IC50 = ~30 nM), as well as significant efficacy in a xenograft flank model (60 day mean tumor size of 1109mm3 [vehicle] vs. 19mm3 [quisinostat-treated]). This in vivo effect was greater than the anti-tumor effect observed in a xenograft flank non-hypermutant DMG model PBT-09 (60 day mean tumor size of 1006mm3 [vehicle] vs. 244mm3 [quisinostat-treated]). To validate the effect of hypermutation on sensitivity to quisinostat, we generated PMS2 knock-out (KO) and MSH2 KO isogenic cell lines using the H3WT model VUMC-DIPG-10. In a xenograft flank model, we observed increased quisinostat sensitivity in the KO models (20 day mean tumor volume of 547mm3 [parental], 396mm3 [PMS2 KO], and 150mm3 [MSH2 KO]). RNA sequencing of quisinostat-treated PBT-24 revealed an increase in acute inflammatory response genes which we are investigating as a mechanism of action for HDACi against hypermutant tumors. Ultimately, we demonstrate the in vivo efficacy of quisinostat against hypermutant DIPG that supports the investigation of HDAC inhibition as a treatment strategy across hypermutant CNS tumors.